The invention relates to a method for producing a hyperpolarized sample for use in a magnetic resonance investigation.
NMR (NMR: nuclear magnetic resonance) techniques may be applied to gather information about a sample or sample area in a gentle, non-destructive way; in particular, clinical investigations on living patients can be done non-invasively. However, NMR techniques are generally limited by low signal intensities.
One way to increase signal intensities is to apply hyperpolarization techniques. Here, nuclei in a sample are prepared with a polarization level higher than corresponding to the Boltzmann distribution at the sample's temperature, and the hyperpolarized nuclei undergo an NMR experiment. In many NMR experiments, information about low γ/high T1 nuclei, respectively, are of particular interest, above all about 13C and 15N (γ: gyromagnetic ratio or gamma; T1: longitudinal relaxation time).
An important hyperpolarization technique is Dissolution DNP (DNP: dynamic nuclear polarization). In a conventional Dissolution DNP experiment, see e.g. WO1999/035508 A1 or WO 2002/037132 A1, the polarization parameters are chosen to directly polarize the nucleus of interest, typically a low gamma/long T1 nucleus such as 13C, with microwave radiation. After polarization, the low temperature solid sample is rapidly heated to room temperature by dissolving it in hot solvent and transferred to the location where it is to be measured by NMR, in particular MRI (MRI: magnetic resonance imaging). In order to minimize polarization losses, it has been proposed to arrange the DNP magnet and the NMR magnet in close proximity to each other, compare WO 2007/007022 A1 or U.S. Pat. No. 7,646,200 B2. In U.S. Pat. No. 8,154,292 B2, a shuttle DNP has been proposed, with a sample moving in its container between two magnetic field regions for Overhauser DNP and NMR spectroscopy, respectively.
One disadvantage of hyperpolarization by DNP is the long polarization time, typically in the order of one hour or more. A potential mitigation of this problem is to polarize 1H nuclei (which is much more rapid) followed by polarization transfer to the low γ nuclei such as 13C through the application of appropriate RF Cross Polarization pulses. This technique has been demonstrated already (A. J. P. Linde, Doctoral thesis, University of Nottingham, November 2009; S. Jannin et. al., Chem. Phys. Lett., 2011, 517, 234) but it poses serious technical challenges with regards to generating sufficiently strong B1 fields at two Larmor frequencies in a cryogenic region.
An important drawback of the latter hyperpolarization method, wherein hyperpolarization is transferred from 1H to 13C in a solid sample, is a relatively high power of the RF Cross polarization pulses which is required to achieve the polarization transfer. The required power limits the amount of sample that can be prepared; in particular, sample sizes typically required for in vivo MRI applications on living human patients cannot be prepared by state of the art equipment.
In a combination of Dissolution DNP on low γ/long T1 nuclei such as 13C or 15N followed by polarization transfer to 1H in the liquid state, protons have been studied with enhanced sensitivity, compare T. Harris et. al., Chem. Eur. J. 2011, 17, 697; R. Sarkar et. al., J. Am. Chem. Soc. 2009, 131, 16014, or M. Mishkovsky et al., Magnetic Resonance in Medicine 2012, 68, 349-352. In these experiments the high polarization levels are largely retained during the dissolution process and the transfer to the NMR magnet because the DNP process was applied to long T1 13C or 15N nuclei. Pulse sequences for such a polarization transfer have been proposed e.g. by G. A. Morris, R. Freeman, J. Am. Chem. Soc. 1979, 101, 760.
It is also known to react parahydrogen molecules with substrate molecules in the liquid phase, and to transfer polarization from the hyperpolarized 1H nuclei of the parahydrogen to low γ nuclei in the substrate molecule. Variants of this PHIP technique (PHIP: ParaHydrogen Induced Polarization) have been disclosed in WO 2004/19995 A2, WO 2004/19996 A1 and WO 2004/19997 A1. It is also known to transfer polarization form parahydrogen to a substrate molecule in the liquid phase in a catalytic process, compare WO 2008/155093 A1. However, hyperpolarization using parahydrogen is potentially hazardous with respect to the handling of hydrogen gas and less general than DNP, in particular with PHIP requiring precursor molecules providing unsaturated bonds.
In Brute Force hyperpolarization the nucleus of interest is polarized by generating very large thermal polarization at very low temperature and in a very strong magnetic field, followed by rapid heating of the sample. The problem of slow polarization build-up in these techniques is particularly serious because of the exceedingly large T1 values at low temperature, especially for low γ spin ½ nuclei such as e.g. 13C. In a proposed implementation of Brute Force hyperpolarization, see WO 2011/026103 A2, the nucleus of interest is hyperpolarized indirectly by generating very large thermal proton polarization at very low temperature, followed by low field nuclear thermal mixing.
It is the object of the invention to provide a method which can provide samples with hyperpolarized long T1 nuclei, in particular 13C or 15N, in a simple and efficient way.